Schizophrenia is a debilitating psychiatric disorder that affects about 0.7% of the global population. Symptoms of schizophrenia can be grouped into three categories: positive symptoms, including hallucinations and delusions;negative symptoms, such as social isolation and flattened affect;and cognitive symptoms, which include impaired attention and working memory. These cognitive deficits comprise a core component of the disease and often prevent schizophrenia patients from integrating into society. Currently available antipsychotic therapies are effective at ameliorating positive symptoms of schizophrenia. However, these drugs often cause serious side effects and are not effective at treating the negative or cognitive symptoms of the disease, which thus represent a major unmet medical need. A primary reason for the lack of more effective treatments for schizophrenia is our poor understanding of the molecular mechanisms underlying the disease. Based upon our functional and behavioral characterization of the forebrain-specific calcineurin knockout mouse, we have developed a novel disease hypothesis for the cognitive deficits of schizophrenia in which a disruption of synaptic vesicle cycling leads to impairments of the neuronal and network activities in prefrontal cortex that are necessary to support working memory. These data are in line with an increasing number of findings from multiple experimental modalities indicating that altered presynaptic function contributes to the etiology of schizophrenia. Our hypothesis predicts that compounds that can restore aberrant neuronal presynaptic function should comprise effective therapies for the cognitive symptoms of schizophrenia. To create a method for identifying compounds with this desired property, we have designed and constructed a novel presynaptic high throughput screening technology with which we can analyze the effects of compounds on synaptic vesicle cycling in neuronal cultures in 96-well plates. The objective of this proposal is to utilize this new technology platform to screen a library of compounds, identify modulators of synaptic vesicle cycling and advance selected compound series to achievement of proof-of-concept in relevant animal models and a mature stage of lead optimization. Upon achievement of the scientific goals of this proposal, we intend to partner the platform technology and identified compounds with a large pharmaceutical corporation to expedite further advancement of this program. Accomplishment of the proposed research will directly contribute to the development of a novel, first-in-class, mechanism-based therapy for the cognitive symptoms of schizophrenia. This advance would have a major positive impact on the lives of schizophrenia patients and their family members. In addition, this proposal supports the mission of economic stimulus by providing new jobs for multiple scientists and supporting the emergence of a new technology and the subsequent development of a new class of valuable medicinal products. PUBLIC HEALTH RELEVANCE: We have discovered a new disease mechanism for the cognitive deficits in schizophrenia. Based on this finding, we have developed a novel screening technology with which we can identify new classes of candidate drugs for treatment of schizophrenia. In particular, the research outlined in this proposal will support the identification of new therapies for the cognitive deficits in schizophrenia, which comprise a major unmet medical need. This research will thus have a positive impact on the significant population of schizophrenia patients and their family members and caregivers, which includes many millions of people worldwide. In particular, improving the cognitive outcome in schizophrenia will help patients to improve their job performance and to integrate into society more effectively.